Synthesis of a 3,4-dihydroxy-1-cyclopentanylpurinone

ABSTRACT

Synthesis of the triol of the following formula (I) from an alcohol of the formula (IV): ##STR1## via steps including protecting and then cyanating the alcohol to yield a cyanide, isomerization of the double bond, hydrolysis followed by reduction of the cyanide back to an alcohol and cis-dihydroxylation of the double bond.

BACKGROUND OF THE INVENTION

Carbocyclic analogues of nucleosides are described in European PatentApplication Publication No. 345,076 published Dec. 6, 1989 as beinguseful as pharmaceuticals in the treatment of viruses, especiallyHerpetoviridae. A particular compound described is (1'S, 3'S,4'S)-2-amino-1,9-dihydro-9-[3,4-dihydroxy-3-(hydroxymethyl)-1-cyclopentyl]-6H-purin-6-oneof the following formula (I): ##STR2##

European Patent Application Publication No. 349,242 published Jan. 3,1990 assigned to the Wellcome Foundation teaches 6-substituted purinecarbocyclic nucleosides and Example 45 provides a synthesis of(±)-9-[3-(hydroxymethyl)-3-cyclopenten-1-yl)guanine (racemic compound offormula (X)). A process for synthesizing2-amino-1,9-dihydro-9-[2,3-dihydroxy-4-(hydroxymethyl)-1-cyclopentanyl]-6H-purin-6-oneis taught in U.S. Pat. No. 5,110,926 using hydrolysis as a final step.U.S. Pat. No. 5,233,041 teaches the synthesis of (1'S, 3'S,4'S)-2-amino-1,9-dihydro-9-[3,4-dihydroxy-3-(hydroxymethyl)-1-cyclopentanyl]-6H-purin-6-oneusing a Swern oxidation. U.S. Pat. No. 5,126,452 teaches the synthesisof (-)-carbovir,2-amino-1,9-dihydro-9-[3-(hydroxymethyl)-1-cyclopentenyl]-6H-purin-6-one.

SUMMARY OF THE INVENTION

Synthetic steps and intermediates involved in a reaction scheme ofconverting a compound of the following formula (IV) to the triol of thefollowing formula (I): ##STR3## The individual steps include protection,sulfonation and cyanation of the alcohol of formula (IV) to yield acyanide, isomerization of the double bond to be in conjugation with thenitrile, deprotection followed by hydrolysis and reduction to an alcoholfollowed by cis-dihydroxylation of the double bond.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes the method of synthesizing a triol of thefollowing formula (I): ##STR4## or an acid- or base-addition saltthereof, which comprises the steps of: i) reacting a cyclopentene of thefollowing formula (II): ##STR5## wherein R=C₁₋₆ alkyl or OC₁₋₆ alkyl,with a purine of the following formula (III): ##STR6## to yield analcohol of the following formula (V): ##STR7## wherein Pro is an aminoprotecting group, ii) cyanating the alcohol of formula (V) to yield thecyanide of the following formula (VIII): ##STR8## iii) deprotecting,hydrolyzing, and then reducing the cyanide of formula (VIII) to yieldthe monoalcohol of the following formula (X): ##STR9## iv)cis-dihydroxylatingon the monoalcohol of formula (X) to produce thetriol of formula (I).

Reaction Scheme 1 which follows sets forth the overall sequence of stepswhich may be used in carrying out the invention. The compound of formula(IV) in the following Reaction Scheme 1 is reacted with an amineprotecting reagent whereby the amino function cannot react withreactants in the subsequent steps. Thus, Pro in formulae (V), (VI),(VII) and (VIII) represents a moiety bound by a double bond, or 2moieties bound by 2 single bonds, to the pendent amino nitrogen, e.g.═CN(CH₃)₂ or --H and --CHO. Although various amine protecting groups canbe used, use of an aminal, also known as an amidine or formamide, hasthe added benefit of rendering the molecule more soluble in organicsolvents so as to allow the subsequent reactions to proceed morereadily. Reaction with the amine protecting group reagent can be atabout 0° to 35° C. in an organic solvent such as methanol, benzene, ordimethylformamide. Removal of the amine protecting group can be carriedout by techniques including acid- or base-catalized hydrolyses orhydride reduction. In more detail the hydrolysis can be carried out withacids such as hydrochloric acid and sulfuric acid and the like or basessuch as potassium hydroxide, sodium hydroxide, sodium methoxide, and thelike or pyridine and triethylamine and the like in protic solvents suchas water, methanol, ethanol, and the like. An amine protecting group═CN(CH₃)₂ can also be removed by hydride reduction with metal hydridessuch as sodium borohydride and the like in protic solvents water,methanol, ethanol, and the like. ##STR10## The cyclopentene of formula(II) is reacted with the purine of formula (III) to give the alcohol offormula (IV). The amine substituent of the compound of formula (IV) isthen reacted with an amine protecting reagent such as dimethylformamidedimethylacetal to yield the alcohol of formula (V), e.g. where Pro is aformamidine group.

From formula (V), the compound of formula (VI) is produced bysulfonation, in particular via a substitution with a methanesulfonyl orp-toluenesulfonyl moiety, also known as mesyl or tosyl groups, toproduce the mesylate or tosylate. Reagents for this reaction includepyridine, methylene chloride and methanesulfonic anhydride orp-toluenesulfonic anhydride, which may be reacted at a temperature of-15° to 15° C. The compound of formula VI is shown in brackets toindicate that it may not be isolatable. The compound of formula (VI) isthen converted to the cis-trans mixture of the cyanide of formula (VII)by reaction with a cyanide ion from the phase transfer catalyst producedby the reaction of acetone cyanohydrin and1,8-diazabicyclo[5.4.0]undec-7-ene. Isomerization of the cyclopentenedouble bond into conjugation with the nitrile may be carried out in a1,8-diazabicyclo[5.4.0]undec-7-ene/hydrogen cyanide buffered organicphase to produce the compound of formula (VIII).

Deprotection of the amino substituent of the compound of formula (VIII)to a compound of formula (IX) where R² is --CN is conducted in thepresence of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid ora similar strong acid at about 60° to 90° C. The cyanide of formula (IX)where R² is --CN may be hydrolyzed to the carboxylic acid of formula(IX) where R² is --COOH. The carboxylic acid of formula (IX) where R² is--COOH may then be converted to the ester of formula (IX) where R² isCOOCH₃, e.g. in the presence of methanol and sulfuric acid at atemperature of 60° to 90° C. Alternatively, the cyanide of formula (IX)where R² is --CN may be hydrolyzed to the compound of formula (IX) whereR² is --COO(CH₂)₂ CH₃. Hydrolyzing the cyanide of formula (IX) to thecarboxylic acid of formula (IX) may be carried out in the presence ofaqueous sodium hydroxide at a temperature of 60° to 90° C. Hydrolizingthe cyanide to the acid may also be carried out with potassiumhydroxide, triethylamine or a similar organic or inorganic base.Hydrolyzing the cyanide of formula (IX) to the compound of formula (IX)where R² is --COO(CH₂)₂ CH₃ may be carried out in the presence ofpropanol and sulfuric acid at a temperature of 85° to 115° C. Thecompound of formula (IX) where R² is --COOCH₃ or --COO(CH₂)₂ CH₃ isreduced in the presence of methylene chloride and diisobutylaluminumhydride at about -10° to 35° C. to give the compound of formula (X).

The compound of formula (X) may then be specifically1,2-cis-dihydroxylated with a catalyst such as osmium tetroxide (OsO₄)and an oxygen source to afford a compound of the formula (I). Reviews ofosmium tetroxide oxidations include those of Martin Schroeder inChemical Reviews, 1980, 80, pp187-213 and V. VanRheenen in TetrahedronLetters, No.23, pp1973-1976. In general, the reaction of (X) to (I) maybe conducted in an H₂ O: acetone mixture having a ratio of 1:1 to 50:1,at about 0 to 100° C., e.g. 23° C., with about 0.008 to 1 equivalent ofosmium tetroxide and an oxygen source such as hydrogen peroxide,N-methylmorpholine N-oxide, a metal chlorate, t-butyl hydroperoxide,sodium peroidate, oxygen gas or sodium hypochlorite.

Also part of the present invention are novel intermediates, e.g.formulae (IV), (V), (VI), (VII), (VIII), and (IX) and all enantiomersand diastereomers thereof.

Further parts of the present invention include triols of formula (I) inthe form of the i) hydrochloride, ii) hydrochloride monohydrate, iii)hemihydrochloride monohydrate. The hydrochloride monohydrate isparticularly important since it has a relatively lower melting pointthan other salts, is not hydroscopic and becomes increasingly purethrough repeated recrystallizations and is thus suitable for use as anactive ingredient in a formulated pharmaceutical.

The present invention also covers the individual enantiomers of thecompounds represented by Reaction Scheme 1 above as mixtures withdiastereoisomers thereof in which one or more stereocenters is inverted.

In the following Examples and throughout the specification, thefollowing abbreviations may be used: mg (milligrams); g (grams); ml(milliliters); hr (hours); min (minutes); mp (melting point); mmole(millimoles); MeOH (methanol); and DMSO (dimethyl sulfoxide); CH₂ CL₂(methylene chloride); DMF (dimethylformamide). Unless otherwise noted,all temperatures are expressed in °C. (degrees centigrade).

EXAMPLE 1 2-Amino-6-chloropurine Sodium Salt (Formula (III))

A 2L round bottomed flask was charged with 100 g (0.59 mole) of2-amino-6-chloropurine and 1L of methanol. To the stirred slurry wasadded a 137 mL (0.59 mole) of a 4.3M solution of sodium methoxide inmethanol. The slurry became homogeneous after stirring for 15 minutes at23° C. The reaction mixture was stirred an additional 15 minutes, thenvacuum filtered through paper. The filtrate was transfered to a 2L roundbottom flask and the solvent volume was reduced to 370 ml to inducecrystallization. To complete crystallization, 500 mL of diethyl etherwas added to the stirred slurry over 30 minutes. The solids werecollected by vacuum filtration, washed with 100 mL of diethyl ether anddried under vacuum (0.5 mm, 23° C.) for 12 hrs to yield 93 g (82%) of2-amino-6-chloropurine sodium salt. mp>280° C.

EXAMPLE 2(1'R-cis)-2-Amino-1,9-dihydro-9-[4-hydroxy-2-cyclopenten-1-yl]-6-chloropurineDimethylaminal (Formula (V)) a.(1'R-cis)-2-Amino-1,9-dihydro-9-[4-hydroxy-2-cyclopenten-1-yl]-6-chloropurine(formula (IV))

To a 500 mL round bottomed flask containing a solution of 1.62 g (1.80mmole) of tris(dibenzylideneacetone)dipalladium (0) in 105 mL oftetrahydrofuran was added 1.8 mL (22.1 mmole) of chloroform. The deepviolet solution was stirred at 23° C. for 2 minutes, then 3.71 g (14.2mmole) of triphenylphosphine was added. The solution turned amber incolor while stirring at 23° C. After 15 minutes, a solution of 17.0 g(88.5 mmole) of 2-amino-6-chloropurine sodium salt, prepared as inExample 1, in 105 mL of dimethylformamide was added followed by the neataddition of 15.1 g (106 mmole) of (+)-(1R-cis)-4-cyclopentene-1,3-diolmonoacetate of formula (II). The reaction mixture was stirred at 23° C.for 75 minutes, then poured into a 4 L separatory funnel containing 400mL of 2.4N aqueous hydrogen chloride. The aqueous solution was washedtwo times with 250 mL of methylene chloride, then with 250 mL of ethylacetate. The organic extracts were discarded. The pH of the aqueoussolution was adjusted to 7 with 70 mL of 30% aqueous ammonium hydroxide.The aqueous solution was extracted 5 times with 250 mL of ethyl acetate.The combined organic extracts were dried over 25 g of magnesium sulfate,filtered and concentrated to give 26.2 g of crude(1'R-cis)-2-Amino-1,9-dihydro-9-[4-hydroxy-2-cyclopenten-1-yl]-6-chloropurineof formula (IV) as an oil contaminated with dimethylformamide (2.5 eq by¹ H NMR).

b.(1'R-cis)-2-amino-1,9-dihydro-9-[4-hydroxy-2-cyclopenten-1-yl]-6-chloropurinedimethytlaminal (Formula (V))

26.2 g of crude(1'R-cis)-2-Amino-1,9-dihydro-9-[4-hydroxy-2-cyclopenten-1-yl]-6-chloropurine,prepared as in Example 2a., as an oil contaminated withdimethylformamide (2.5 eq by ¹ H NMR) was dissolved in 450 mL ofacetonitrile then transferred to a 1 L round bottomed flask equippedwith a magnetic stir bar and reflux condenser. The reaction vessel wasplaced in an oil bath preheated to 65°-70° C. and 12.9 mL (97.5 mmole)of dimethylformamide dimethylacetal was added. The solution was stirredat 65° C. for 30 minutes. To induce crystallization, the solvent volumewas reduced to 125 mL. To complete crystallization, the slurry wascooled to 0° C. while stirring and 100 mL of a 1:1 solution of diethylether/hexane was added over 30 minutes. The slurry was stirred at 0° C.for 2 hours, the crystals were collected by vacuum filtration and driedunder vacuum (0.5 mm, 23° C.) for 15 hours to yield 12.6 g (46%) of thetitle compound.

mp 187°-189° C.

[α]_(D) +202° (c 0.0966, CH₂ Cl₂).

Analysis Found: C (51.02), H (4.98), N (27.23), Cl (11.74);

C₁₃ H₁₅ ClN₆ O requires: C (50.90), H (4.93), N (27.40), Cl (11.56).

EXAMPLE 3(1'S)-2-Amino-1,9-dihydro-9-[4-cyano-3-cyclopenten-1-yl]-6-chloropurineDimethylaminal (formula (VIII))

A 1L round bottomed flask equipped with a magnetic stir bar and gasinlet vented through a nitrogen atmosphere was charged with 12.2 g (39.8mmole) of(1'R-cis)-2-amino-1,9-dihydro-9-[4-hydroxy-2-cyclopenten-1-yl]-6-chloropurinedimethytlaminal, prepared as in Example 2, 11.0 g (139 mmole) ofpyridine and 180 mL of methylene chloride. The solution was cooled to 0°C. under an atmosphere of nitrogen. A solution of 13.9 g (79.5 mmole) ofmethanesulfonic anhydride in 60 mL of methylene chloride was added tothe stirred solution over 1 minute. The reaction mixture was stirred at0° C. for 20 minutes to give a compound of formula (VI), then 27.1 g(318 mmole) of acetone cyanohydrin was added at once, followed by adropwise addition of 36.3 g (239 mmole) of1,8-diazabicyclo[5.4.0]undec-7-ene over 5 minutes. The amber coloredreaction mixture turned nearly black on addition of the1,8-diazabicyclo[5.4.0]undec-7-ene. The solution was warmed to 23° C.and stirred 2 hours. The reaction mixture was poured into a separatoryfunnel containing 300 mL of water. The pH of the aqueous layer wasadjusted to 6-7 with hydrochloric acid. The separatory funnel wasshaken, and the pH readjusted to 6-7. This process was repeated until aconstant pH of 6-7 was maintained in the aqueous layer (30 mL of 12Nhydrochloric acid was used). The aqueous and organic layers wereseparated and the aqueous extract was washed with 300 mL of methylenechloride. The combined organic extracts were washed with 100 mL ofsaturated, aqueous sodium chloride, dried over 25 g of magnesiumsulfate, filtered and concentrated to a dark colored oil. The oil wastriturated with 120 mL of 3:1 hexane:diethyl ether. The solvent wasdecanted providing 21 g of crude (1'S)-2-amino-1,9-dihydro-9-[4-cyano-3-cyclopenten-1-yl]-6-chloropurine dimethylaminal of formula(VIII) as a semi-solid. The semi-solid was dissolved in 150 mL ofmethylene chloride and vacuum filtered through a 1.5 inch bed of silicagel (50 g). The silica bed was washed four times with 150 mL of 99.5:0.5methylene chloride:methanol. The filtrates were combined, andconcentrated to an oil. Trituration of the oil with 125 mL of diethylether provided a solid. The ether was decanted and the solid was driedunder vacuum (0.5 mm, 23° C.) for 18 hours to yield 7.6 g (60.8%) of(1'S)-2-amino-1,9-dihydro-9-[4-cyano-3-cyclopenten-1-yl]-6-chloropurinedimethylaminal of formula (VIII). Then 300 mg of this material wasdissolved in 25 mL of methanol. The solution was decolorized with 0.5 gof activated carbon (Darco G-60), vacuum filtered through paper and thefiltrate was concentrated to give 180 mg of(1'S)-2-amino-1,9-dihydro-9-[4-cyano-3-cyclopenten-1-yl]-6-chloropurinedimethylaminal of formula (VIII) as a colorless foam. The foam wasdissolved in 15 mL of hot ethyl acetate. To induce crystallization, thesolvent volume was reduced to 10 mL, and to complete crystallization, 5mL of hexane was added. The crystals were collected by vacuum filtrationand dried under vacuum (0.5 mm, 23° C.) for 15 hours to yield 105 mg ofthe title compound.

mp 177°-180° C.

[α]_(D) +74° (c 0.21, MeOH).

Analysis Found: C(53.21), H(4.51), N(30.99), Cl(11.31); C₁₄ H₁₄ ClN₇requires: C(53.25), H(4.47), N(31.05), Cl(11.23).

EXAMPLE 4(1'S)-2-Amino-1,9-dihydro-9-[4-cyano-3-cyclopenten-1-yl]-6H-purin-6-one(Formula (IX), R² =-CN)

A 250 mL round bottomed flask equipped with a reflux condenser andmagnetic stir bar was charged with 7.15 g (22.6 mmole) of(1'S)-2-amino-1,9-dihydro-9-[4-cyano-3-cyclopenten-1-yl]-6-chloropurinedimethylaminal, prepared as in Example 3, and 100 mL of 3N hydrochloricacid. The reaction vessel was placed in an oil bath preheated to 75° C.and stirred for 2.5 hours. The dark colored solution was decolorizedwith 4 g of activated carbon (Darco G-60), then filtered through paper.The charcoal was washed with 50 mL of 3N aqueous hydrogen chloride. Thefiltrates were combined, and heated to 75° C. To effect crystallization,the pH of the solution was adjusted to 7 with 33 mL of 30% aqueousammonium hydroxide. To complete crystallization, the reaction slurry wascooled to 23° C. over 30 minutes, then to 0° C. and stirred for 2 hours.The solids were collected by vacuum filtration, washed with 40 mL of 0°C. cooled deionized water, then dried under vacuum (0.5 mm, 23° C.) for15 hours to yield 3.52 g of(1'S)-2-amino-1,9-dihydro-9-[4-cyano-3-cyclopenten-1-yl]-6H-purin-6-oneof formula (IX) where R¹ =-CN in 64% yield. Then 130 mg was trituratedwith 5 mL of 100° C., deionized water for 30 minutes, then cooled to 23°C. The solids were collected by vacuum filtration and dried under vacuum(0.5 mm, 23° C.) for 24 hours to yield 110 mg of the title compound.

mp>280° C.

[α]_(D) +41° (c 0.126, DMF).

Analysis Found: C(53.38), H(4.21), N(34.02); C₁₁ H₁₀ N₆ O-0.25H₂ Orequires: C(53.54), H(4.29),, N(34.06).

EXAMPLE 5(1'S)-2-Amino-1,9-dihydro-9-[4-carboxyl-3-cyclopenten-1-yl]6H-purin-6-one(Formula (IX), R² =--COOH)

A 250 mL round bottomed flask equipped with a reflux condenser andmagnetic stir bar was charged with (3.24 g (13.3 mmole) of(1'S)-2-amino-1,9-dihydro-9-[4-cyano-3-cyclopenten-1-yl]-6H-purin-6-one,prepared as in Example 4, 7.27 g (182 mmole) of sodium hydroxide and 40mL of deionized water. The reaction flask was placed in an oil bathpreheated to 75° C. and stirred for 75 minutes. The hot solution wasvacuum filtered through paper and the filtrate was returned to a 250 mLround bottomed flask equipped with a magnetic stir bar. To inducecrystallization, the pH of the aqueous solution was carefully adjustedto 3.5 by adding 17 mL of 36% hydrochloric acid. The reaction slurry wasstirred for 30 minutes as it cooled to 23° C. To completecrystallization, the slurry was cooled to 0° C. and stirred for 2 hours.The crystals were collected by vacuum filtration, washed with 10 mL of0° C., deionized water, then 10 mL of ethanol. The crystals were driedunder vacuum (0.5 mm, 23 C) for 18 hours to afford 2.77 g (79%) of thetitle compound,

mp>280° C.

[α]_(D) +11°±1 (c 0.19, DMF).

Analysis Found: C (48.99), H(4.28), N (25.90); C₁₁ H₁₁ N₅ O₃ -0.5H₂ Orequires: C(48.89), H(4.47), N(25.91).

EXAMPLE 6 Synthesis of(1'S)-2-Amino-1,9-dihydro-9-[4-carbomethoxy-3-cyclopenten-1-yl]-6H-purin-6-one(Formula (IX), R² =--COOCH₃)

A 250 mL round bottomed flask equipped with a relux condenser vented tonitrogen atmosphere and magnetic stir bar was charged with 2.70 g (10.3mmole) of(1'S)-2-amino-1,9-dihydro-9-[4-carboxyl-3-cyclopenten-1-yl]6H-purin-6-one,prepared as in Example 5, 60 mL of methanol and 1.22 g (12.4 mmole) ofconcentrated sulfuric acid. The reaction solution was placed in an oilbath preheated to 75° C. and stirred for 5.5 hours. The hot reactionmixture was vacuum filtered though paper and the filtrate was transferedto a clean, 250 mL round bottomed flask. The reaction vessel was placedin an oil bath preheated to 65° C. and 1.46 g (14.5 mmole) oftriethylamine was added to liberate(1'S)-2-amino-1,9-dihydro-9-[4-carbomethoxy-3-cyclopenten-1-yl]-6H-purin-6-onefrom its sulfate salt. To induce crystallization, the reaction mixturewas cooled to 23° C. and stirred for 15 hours. The crystals werecollected by vacuum filtration, washed with 10 mL of methanol and driedunder vacuum (0.5 mm, 23° C.) for 3 hours to yield 2.5 g (88%) of thetitle compound.

mp 280°-281° C.

[α]_(D) +11° (c 0.15, DMF).

Analysis Found: C (52.36), H(4.81), N (25.34);

C₁₂ H₁₃ N₅ O₃ requires C(52.36), H(4.76), N(25.44).

EXAMPLE 7(1'S)-2-Amino-1,9-dihydro-9-[4-(carbo-1-propyloxy)-3-cyclopenten-1-yl]-6H-purin-6-one(Formula (IX), R² =--COO(CH₂)₂ CH₃)

A 500 mL round bottomed flask equipped with a magnetic stir bar andreflux condenser vented to a nitrogen atmosphere was charged with 10.0 g(41.3 mmole) of(1'S)-2-amino-1,9-dihydro-9-[4-cyano-3-cyclopenten-1-yl]-6H-purin-6-one,prepared as in Example 4, 150 mL of 1-propanol and 11 mL (206 mmole) ofsulfuric acid. The slurry was heated to 100° C. and stirred at thattemperature for 48 hours. The slurry became homogeneous at 90°-100° C.The reaction flask was removed from the heat source and 31.6 mL (227 mL)of triethylamine was added. To induce crystallization, 200 mL ofdeionized water was added over 5 minutes. The slurry was cooled to 23°C. and stirred for 60 minutes, then to 0° C. and stirred for 4 hours.The solid was collected by vacuum filtration, washed with 10 mL ofdeionized water and dried under vacuum (0.5 mm, 23° C.) for 18 hours toafford 12.5 g (63%) of the title compound.

mp 256°-258° C.

[α]_(D) +16±1° (c 0.033, methanol).

Analysis Found: C (52.18), H(6.00), N (21.73);

C₁₄ H₁₇ N₅ O₃ -H₂ O requires: C(52.33), H(5.96), N(21.79).

EXAMPLE 8(1'S)-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-3-cyclopenten-1-yl]-6H-purin-6-one(Formula (X))

A 3-necked, 2L round bottomed flask equipped with a reflex condenservented to a nitrogen atmosphere, addition funnel, thermometer andmechanical stirred was charged with 22.7 g (82.5 mmole) of(1'S)-2-amino-1,9-dihydro-9-[4-carbomethoxy-3-cyclopenten-1-yl]-6H-purin-6-one,prepared as in Example 6, and 100 mL of methylene chloride. The slurrywas cooled to 5° C. and 288 mL (288 mmole) of 1M diisobutylaluminumhydride in methylene chloride was added dropwise over 5 minutes. Thereaction mixture was stirred at 0° C. for 10 minutes, then warmed to 23°C. and stirred for 20 minutes. Excess diisobutylaluminum hydride wasquenched by the gradual addition of 20 mL of 85:15 methanol:acetic acid.The reflux condenser was replaced with a short path distillation headand the reaction mixture was slowly heated to reflux to distill out themethylene chloride. To avoid gelling, a reaction volume of 1000 mL wasmaintained by a gradual addition of 1050 mL of 85:15 methanol:aceticacid as the methylene chloride was removed by distillation (38° C.).When the distillate temperature rose to 65° C., the distillation headwas removed and the reaction vessel was refitted with a reflux condenservented through a nitrogen atmosphere. The heterogeneous reaction mixturewas heated to 65° C., 40 g of diatomaceous earth (Fisher 545) was addedand the slurry was stirred for 36 hours. The hot slurry was vacuumfiltered through an 8 inch filter funnel and the semi-gelatineous solidswere washed three times with 500 mL of methanol. The combined filtrateswere concentrated to a volume of 550 mL, then transfered to a 4 neck, 2L round bottomed flask equipped with a thermometer, mechanical stirrerand addition funnel. To induce crystallization, the reaction mixture washeated to 50° C. and 1 L of methyl t-butyl ether was added dropwise over30 minutes. The slurry was cooled to 23° C. and stirred for 2 hours. Thecrystals were collected by vacuum filtration, washed with 50 mL ofmethyl t-butyl ether and dried under vacuum (0.5 mm, 23° C.) for 15hours to yield 13.06 g of(1'S)-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-3-cyclopenten-1-yl]-6H-purin-6-oneof formula (X). To obtain a second crop of(1'S)-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-3-cyclopenten-1-yl]-6H-purin-6-oneof formula (X) the filtrate volume was reduced to 350 mL and 500 mL ofmethyl t-butyl ether was added. The slurry was stirred at 23° C. for 12hours, the solids were collected by vacuum filtration, washed with 25 mLof methyl t-butyl ether and dried under vacuum (0.5 mm, 23° C.) for 18hours to yield 3.82 g of a second crop of (1'S)-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-3-cyclopenten-1-yl]-6H-purin-6-one of formula (X). Thefirst and second crops were blended to afford 16.88 g (83%) of the titlecompound.

mp>280° C.

[α]_(D) +14° (c 0.18, DMF).

Analysis Found: C (51.74), H(5.42), N (27.37);

C₁₁ H₁₃ N₅ O₂ requires: C(51.56), H(5.51), N(27.33).

EXAMPLE 9(1'S)-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-3-cyclopenten-1-yl]-6H-purin-6-one(Formula (X))

A 4-necked, 1L round bottomed flask equipped with a reflux condenservented to a nitrogen atmosphere, addition funnel, thermometer andmechanical stirred was charged with 7.70 g (25.4 mmole) of(1'S)-2-amino-1,9-dihydro-9-[4-(carbo-1-propyloxy)-3-cyclopenten-1-yl]-6H-purin-6-one,prepared as in Example 7, and 300 mL of methylene chloride. The slurrywas cooled to 5° C. and 88.8 mL (88.8 mmole) of 1M diisobutylaluminumhydride in methylene chloride was added dropwise over 5 minutes. Thesolution was warmed to 23° C. and stirred for 30 minutes. An additional6.35 mL (6.35 mmole) of diisobutylaluminum hydride was added to thereaction mixture, and the solution was stirred for 10 minutes. Excessdiisobutylaluminum hydride was quenched by the gradual addition of 30 mLof 90:10 methanol:acetic acid. The reflux condenser was replaced with ashort path distillation head and the reaction mixture was slowly heatedto reflux to distill out the methylene chloride. To avoid gelling, areaction volume of 400 mL was maintained by a gradual addition of 400 mLof 90:10 methanol:acetic acid as the methylene chloride was removed bydistillation (38° C.). When the distillate temperature rose to 65° C.,the distillation head was removed and the reaction vessel was refittedwith a reflux condenser vented through a nitrogen atmosphere. Theheterogeneous reaction mixture was heated to 65° C., 15 g ofdiatomaceous earth (Fisher 545) was added and the slurry was stirred for38 hours. The hot slurry was vacuum filtered through a 3/4 inch bed ofdiatomaceous earth (Fisher 545) on an 8 inch filter funnel and thesemi-gelatineous solids were washed three times with 300 mL of 90:10methanol:acetic acid. The combined filtrates were concentrated to avolume of 100 mL, then transferred to a 4 neck, 1 L round bottomed flaskequipped with a thermometer, mechanical stirrer and addition funnel. Toinduce crystallization, the reaction mixture was heated to 50° C. and350 mL of methyl t-butyl ether was added dropwise over 30 minutes. Theslurry was cooled to 23° C. over 30 minutes, then to 0° C. and stirredfor 2 hours. The crystals were collected by vacuum filtration, washedwith 50 mL of acetonitrile and dried under vacuum (0.5 mm, 23° C.) for 8hours to yield 4.8 g of(1'S)-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-3-cyclopenten-1-yl]-6H-purin-6-oneof formula (X). To obtain a second crop of(1'S)-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-3-cyclopenten-1-yl]-6H-purin-6-oneof formula (X) the filtrate volume was reduced to 30 mL and 70 mL ofmethyl t-butyl ether was added. The slurry was stirred at 23° C. for 2hours, the solids were collected by vacuum filtration, washed with 5 mLof acetonitrile and dried under vacuum (0.5 mm, 23° C.) for 18 hours toyield 1.06 g of a second crop of(1'S)-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-3-cyclopenten-1-yl]-6H-purin-6-one of formula (X). The first and second crops of(1'S)-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-3-cyclopenten-1yl]-6H-purin-6-one of formula (X) were combined and triturated with 50 mLof acetonitrile at 23° C. for 2 hours. The solid was collected by vacuumfiltration and dried under vacuum (0.5 mm, 23° C.) for 18 hours to yield4.43 g (70%) of the title compound.

mp>230° C. (darkens), mp>280° C.

[α]_(D) +13° (c 0.13, DMF).

EXAMPLE 10(1'S,3'S,4'S)-2-Amino-1,9-dihydro-9-[3,4-dihydroxy-3-(hydroxymethyl)-1-cyclopentanyl]-6H-6-one(Formula (I))

A 250 mL round bottomed flask equiped with a magnetic stir bar andreflux condenser vented through a nitrogen atmosphere was charged with3.35 g (13.5 mmole) of(1'S)-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-3-cyclopenten-1-yl]-6H-purin-6-one,prepared as in Example 8 or 9, 100 mL of deionized water, 20 mL ofacetone and 3.97 g (33.9 mmole) of N-methylmorpholine-N-oxide. Thesolution was placed in an oil bath preheated to 70° C. and 2.15 mL(0.339 mmole) of a 4 wt % solution of osmium tetraoxide in water wasadded via syringe. The reaction mixture was stirred at 70° C. for 30minutes. To decompose the osmium (VI) esters and reduce the higheroxidation osmium (VI, VIII) species, 25 mL of pyridine was added to thereaction mixture followed by hydrogen sulfide gas (purged into thereaction mixture through a fine fritted glass bubbler for 15 seconds).The reaction mixture was stirred at 70° C. and hydrogen sulfide gas waspurged into the reaction mixture for 15 seconds after 5, 17, 28, and 52hours. After stirring a total of 72 hours, 1 g of activated carbon(Darco G-60) was added to the reaction mixture and the hot solution wasvacuum filtered through paper. The carbon was washed with 50 mL ofdeionized water. The filtrate was transfered to a 1 L round bottomedflask and concentrated to a damp, dark solid. The crude solid wastriturated with 40 mL of acetonitrile to remove pyridine andN-methylmorpholine, then collected by vacuum filtration to yield 4.8 gof (1'S,3'S,4'S)-2-amino-1,9-dihydro-9-[3,4-dihydroxy-3-(hydroxymethyl)-1-cyclopentanyl]-6H-6-one as a dark colored solid. The dark solidwas transfered to a 250 mL round bottomed flask equipped with a magneticstir bar and reflux condenser, then dissolved in 160 mL of 4:1 deionizedwater:ethanol. The dark colored solution was heated to 70° C. thentreated with 1.5 g of activated carbon (Darco G-60). The hot slurry wasvacuum filtered through a 1/2 inch bed of diatomaceous earth (10 g) in asteam jacketed filter funnel. The solids were washed with 25 mL ofdeionized water. To induce crystallization, the filtrate volume wasreduced to 70 mL. To complete crystallization, the slurry was stirredfor 1 hour at 23° C., then cooled to 0° C. and stirred 1 hour. Thecrystals were collected by vacuum filtration, washed with 10 mL ofethanol and dried under vacuum (0.5 mm, 23° C.) for 15 hours to yield2.9 g of(1'S,3'S,4'S)-2-amino-1,9-dihydro-9-[3,4-dihydroxy-3-(hydroxymethyl)-1-cyclopentanyl-6H-6-oneof formula (I). To further reduce the osmium content, the 2.9 g of(1'S,3'S,4'S)-2-amino- 1,9-dihydro-9-[3,4-dihydroxy-3-(hydroxymethyl)-1-cyclopentanyl]-6H-6-one of formula (I) was transfered to a 250mL round bottomed flask equiped with a magnetic stir bar and refluxcondenser, then dissolved in 50 mL of deionized water containing 2.65 mLof 36% hydrochloric acid. The reaction flask was placed in an oil bathpreheated to 70° C. and the solution was purged with hydrogen sulfidegas for 30 seconds. The solution was stirred at 70° C. for 20 hours,then vacuum filtered through paper. The filtrate was transfered to a 250mL round bottomed flask, heated to 70° C. and the pH of the solution wasadjusted to 7 by adding 6 mL of 30% aqueous ammonium hydroxide.Activated carbon (Darco G-60, 1 g) was added to the reaction mixture andthe hot solution was vacuum filtered through a 1/2 inch bed ofdiatomaceous earth (10 g) in a steam jacketed filter funnel. The solidswere washed two times with 20 mL of deionized water. The filtrates werecombined in a 250 mL round bottomed flask. To induce crystallization,the solvent volume was reduced to 40 mL, the resulting slurry wasstirred for 1 hour at 23° C., then cooled to 0° C. and stirred for 1hour. The crystals were collected by vacuum filtration, washed with twotimes 10 mL of deionized water, 10 mL of ethanol then dried under vacuum(0.5 mm, 23° C.) for 18 hours to yield 2.33 g (61%) of the titlecompound.

mp>215° C., shrank into decomposition

[α]_(D) +14° (c 0.133, H₂ O)

Analysis Found: C (44.19), H(5.69), N (23.43);

C₁₁ H₁₅ N₅ O₄ -H₂ O requires: C(44.15), H(5.73), N(23.40).

What is claimed is:
 1. A method of synthesizing a triol of the followingformula (I): ##STR11## or an acid- or base-addition salt thereof, whichcomprises the steps of: i) reacting a cyclopentene of the followingformula (II): ##STR12## wherein R is C₁₋₆ alkyl or OC₁₋₆ alkyl, with apurine of the following formula (III): ##STR13## to yield an alcohol ofthe following formula (V): ##STR14## wherein Pro is an amino protectinggroup, ii) cyanating the alcohol of formula (V) to yield the cyanide ofthe following formula (VIII): ##STR15## iii) deprotecting, hydrolyzing,and then reducing the cyanide of formula (VIII) to yield the monoalcoholof the following formula (X): ##STR16## iv) performing acis-dihydroxylation on the monoalcohol of formula (X) to produce thetriol of formula (I).
 2. The method of claim 1, wherein said cyanatingstep ii) comprises the steps of:a) sulfonating an alcohol of thefollowing formula (V): ##STR17## with a sulfonating reagent to yield acompound of the following formula (VI): ##STR18## wherein R¹ is CH₃ orH₃ CC₆ H₄ ; and b) displacing the sulfonyl moiety with a nitrile moietyto yield a cyanide of the following formula (VIII): ##STR19##
 3. Themethod of claim 2, wherein said cyanating step ii) occurs in thepresence of acetone cyanohydrin and 1,8-diazabicyclo[5.4.0]undec-7-ene.4. The method of claim 3, wherein said shifting the cyclopentene doublebond occurs at about -10° C. to +35° C.
 5. The method of claim 1,wherein said deprotecting of step iii) is conducted with hydrochloricacid, sulfuric acid, p-toluenesulfonic acid or a similar strong acid. 6.The method of claim 1, wherein said deprotecting of step iii) isconducted at about 60° to 90° C.
 7. The method of claim 1, wherein saidhydrolyzing of step iii) is conducted with sodium hydroxide, potassiumhydroxide or triethylamine.
 8. The method of claim 1, wherein saidhydrolyzing of step iii) is conducted at about 60° to 90° C.
 9. Themethod of claim 1, wherein said reducing of step iii) is conducted withmethylene chloride and diisobutylaluminum hydride.
 10. The method ofclaim 1, wherein said reducing of step iii) is conducted at about -10°to 35° C.
 11. A method of synthesizing a cyanide of the followingformula (VIII): ##STR20## wherein Pro is an amino protecting group,which comprises the steps of: a) sulfonating an alcohol of the followingformula (V): ##STR21## with a sulfonating reagent to yield a compound ofthe following formula (VI): ##STR22## wherein R¹ is CH₃ or H₃ CC₆ H₄ ;and b) displacing the sulfonyl moiety with a nitrile moiety to yield thecyanide of formula (VIII).
 12. The method of claim 11, wherein saidsynthesizing occurs in the presence of acetone cyanohydrin and1,8-diazabicyclo[5.4.0]undec-7-ene.
 13. The method of claim 12, whereinsaid shifting the cyclopentene double bond occurs at about -10° C. to+35° C.